Alterations of cerebral white matter structure in psychosis and their clinical correlations: a systematic review of Diffusion Tensor
Imaging studies

Alterazioni strutturali della sostanza bianca cerebrale nella psicosi e le relative correlazioni cliniche: una rassegna sistematica degli studi di diffusion
tensor imaging

Serena PARNANZONE1, Dario SERRONE1, maria cristina ROSSETTI1, SIMONA D’ONOFRIO1, alessandra splendiani2, valeria micelli2, ALESSANDRO ROSSI1, FRANCESCA PACITTI1

1Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L’Aquila, Italy
2Department of Biothecnological and Applied Clinical Sciences (DISCAB), Neuroradiological Unit, University of L’Aquila, Italy

SUMMARY. Schizophrenia is a common, severe and chronically disabling mental illness. Most of MRI studies in schizophrenia suggest the involvement of white matter (WM) pathology in multiple cerebral regions in the neurobiology of this condition. White matter fiber tracts connecting numerous cortical regions have been the focus of a number of studies using a magnetic resonance technique called “Diffusion Tensor Imaging” (DTI). A literature search of published DTI studies was conducted using the major database National Centre for Biotechnology information (NCBI) PubMed (MEDLINE). Our review covers 95 published papers. We summarise the main DTI findings involving the different brain regions in patients affected by or at high-risk for psychosis; we discuss clinical implications of these white matter disruptions and the limitations of current studies, listing the potential confounds and suggesting potential future research directions.

Key Words: DTI, psychosis, schizophrenia, white matter.

RIASSUNTO. La schizofrenia è una malattia mentale comune, grave e cronicamente invalidante. La maggior parte degli studi di risonanza magnetica in pazienti affetti da schizofrenia suggerisce il coinvolgimento della sostanza bianca di diverse regioni cerebrali nella patogenesi e nella neurobiologia di questa malattia. I fasci di sostanza bianca interposti tra le diverse regioni corticali sono stati oggetto di numerosi studi che utilizzano una tecnica di risonanza magnetica chiamata “Diffusion Tensor Imaging” (DTI). Nel presente studio è stata condotta una revisione della letteratura sugli studi di DTI pubblicati utilizzando il database National Centre for Biotechnology (NCBI) PubMed (Medline). Questa rassegna comprende 95 articoli pubblicati. Sono stati riportati i principali risultati degli studi di DTI in pazienti affetti da psicosi o ad alto rischio per lo sviluppo di psicosi; sono state discusse le implicazioni cliniche delle alterazioni della sostanza bianca e i limiti degli studi in corso elencando i potenziali fattori di confondimento e suggerendo possibili direzioni future per la ricerca.

Parole Chiave: DTI, psicosi, schizofrenia, sostanza bianca.

Schizophrenia is a complex psychiatric syndrome comprising of psychiatric symptoms, including auditory hallucinations and delusions, cognitive deficits and social dysfunction1.
The majority of studies on structural brain changes in patients at ultra-high risk for or affected by psychosis have been based on magnetic resonance imaging. Brain structural MRI is based on the differential behaviour of protons of water molecules in gray and white matter when exposed to a variable magnetic field. The contrast between structures varying in the response to magnetic field alterations allows delineating local groupings of neurons and fibers and determining their sizes in absolute and relative terms 2.
Most of MRI studies in schizophrenia suggest the involvement of white matter (WM) pathology in multiple cerebral regions in the neurobiology of this condition. As normal brain functions are served by macrostructural circuits of cortical and subcortical areas, disturbed communication between brain regions may be the core pathology of psychosis. WM consists of the axonal projections to other neurons and functional brain areas and is therefore key to neural communication. Myelination is initiated prenatally and completed for most tracts within the first year birth but continues during childhood, adolescence and adulthood and has a region-specific course where prefrontal regions myelinate the last 3. Several lines of evidence point to myelin dysfunction, reduced oligodendrocyte number or integrity, or possibly hyperglutamatergic state4.
Neurodevelopmental theories have suggested demyelination during adolescence and adulthood to occur in psychosis.
Abnormalities in WM structure and integrity have been correlated with psychotic symptoms, negative symptoms and cognitive deficits5.
WM is difficult to study in detail with conventional MRI because of its high degree of homogeneity, moreover conventional techniques do not allow for the evaluation of its directionality and organization. WM fiber tracts connecting numerous cortical regions have been the focus of a number of studies using a magnetic resonance technique called Diffusion Tensor Imaging (DTI). It has become established in the last two decades as a valuable research tool. DTI assesses a non-invasive and in vivo quantification of the diffusion characteristics of water molecules: within a magnetic field these molecules tend to align into preferential directions according to their ability to diffuse across or along the arrangement of biological structures that surround them. In the brain water may diffuse freely in all directions (isotropic diffusion), or restricted along one particular direction of structured tissue such as WM tracts and fibers (anisotropy diffusion). Fractional anisotropy is a quantitative dimension and can take values between 0 and 1. If the anisotropy is high, then most of the diffusion occurs in the highly ordered directions, indicating a high level of orientation in the structure, therefore, decreased anisotropy may predict compromised white matter integrity 6. Other measures used to compare different voxels in term of diffusion are mean diffusivity (MD), radial diffusivity (RD) and relative anisotropy (RA)7. Additionally different approaches have been applied to study differences in regional brain anisotropy between subjects: some studies have used voxel based approaches (VBA), where data sets have been processed with reference to FA normalized to a standard anatomical and averaged template, before being compared to similarly processed data sets; other studies have used a region of interest (ROI) approach in region of the brain thought to be implicated to psychosis. DTI is becoming increasingly important in the field of schizophrenia research 8.
The aim of this study was to review the knowledge about the abnormalities of WM in patients at ultra-high risk for psychosis (UHR), patients with a first-episode psychosis (FEP) and chronic schizophrenia patients (SZ) compared with controls (HC), making clearer the role of WM integrity alterations in the etiopathogenesis, anatomical bases and clinical or neuro-cognitive correlates of the disorders.
A literature search of published DTI studies was conducted using the major database National Centre for Biotechnology information (NCBI) PubMed (Medline).
The key words used were: “schizophrenia” and “ DTI” or “diffusion tensor imaging”, “psychosis” and “DTI” or “diffusion tensor imaging”. Studies were included if they satisfied the following criteria: the patient population had a diagnosis of psychosis or was considered at ultra-high risk for psychosis, diffusion tensor imaging was an imaging technique used, the article was published in English. Additionally, they were chosen if they were found to be relevant to the focus of this systematic review.
Our review covers 95 papers published between September 2005 and March 2015: 32 papers were excluded.
In 25 studies the patient population included people considered at ultra-high risk for psychosis. To be considered at high-risk for psychosis patients had to satisfy almost one of these criteria: 1) they had schizotypal personality features; 2) they had sub-threshold psychotic symptoms; 3) they had a first-degree relative with schizophrenia-like disorder; 4) they had brief psychotic moments with spontaneous remission in less than 1 week (Table 1).
We have decided to mention some of the studies excluded because they can provide additional information.
In a study was examined the ability of DTI to differentiate between UHR, FEP and HC subjects: the results suggest that DTI allowed discrimination of UHR from HC subjects34.
Patients with only cannabis use disorder (CUD) have also been studied with DTI method: they had lower FA than HC in left inferior FOF27, and altered FA values in left ILF and left inferior FOF compared to HC; greater consumption of cannabis predicted a greater decrease in left ILF FA in CUD35.
In the study by Mittal et al.36 youth at high-risk for psychosis presented neurological disfunction and abnormal neurodevelopment misured by the presence of neurological soft signs (NSS) and a decrease of FA in right/left superior CP at 12 months, controls showed a normative increase while there were no group differences at baseline. NSS predicted a longitudinal decrease in cerebellar-thalamic FA and elevations in negative but not positive symptoms 12 months later.
According to Derosse et al.37 cumulative risk for psychosis (including low QI, low parental socioeconomic status, history of adolescent cannabis use and childhood trauma, high levels of subclinical psychotic-like experiences) was associated with lower FA in left SLF.
In the study by Skranes et al.38 very low birth weight children had reduced FA values in CI, CE, CC, ILF, SLF; children with low QI had reduced FA in CE, SLF, ILF; fine motor impairment was related to low FA in CI, CE and SLF; mild social deficits correlated with reduced FA in CE and SLF.
Prenatal and neonatal DTI were obtained in the offspring of mothers with schizophrenia or schizoaffective disorder and matched comparison mothers: there were no group differences in white matter diffusion tensor properties39.
In 41 studies the patient population included people experiencing a first episode of psychosis. (Table 2)
According to Peters et al.75 FEP with cannabis use before age 17 showed increased directional coherence in the bilateral UF, anterior CI and FL while these abnormalities were absent in FEP without cannabis use before age 17: this is in contrast with most DTI studies which have produced evidence of WM hypoconnectivity.
In 46 studies the patient population included people with chronic schizophrenia (Table 3).
Tang et al.110 obtained DTI and magnetic resonance spectroscopy from 40 subjects with schizophrenia: N-Acetylaspartate and DTI anisotropy indices were reduced in medial temporal regions.
Patients with temporal lobe epilepsy and interictal psychosis were studied with DTI by Flügel et al.111; they showed lower FA values in both frontal and temporal regions and higher MD in bilateral frontal regions, additionally the performance on some neuropsychological tests was related to frontotemporal FA reduction. Mao et al.112 investigated interictal personality changes and white matter abnormalities in epilepsy patients: long disease duration and impairment of right AF integrity were independent risk factor of psychoticism.
Cocchi et al.113 studied the relationship between structural and functional deficits in schizophrenia patients: they showed decreased functional connectivity and impaired white matter integrity in a distributed network encompassing frontal, temporal, thalamic and striatal regions; in controls strong interregional coupling in neural activity was associated with well-myelinated white matter pathways.
Compared with Parkinson’s disease patients without psychosis, those with psychosis had significantly lower FA in left frontal lobe, bilateral occipital lobe, left cingulated gyrus and left hippocampus114.
For an overview of the results see table 4.

The findings can be grouped into WM pathology affecting cortical regions, subcortical regions, inter-hemispheric fibers, association fibers and limbic system fibers. Corpus callosum consists of a commissural tract comprising the largest bundle of fibers connecting the two brain hemispheres.
Association fibers are: SLF which connects the frontal lobe with occipital and temporal areas, ILF, UF which are anterior temporo-frontal fiber tracts connecting orbito-frontal with anterior and medial temporal lobes, FOF which extends backward from the frontal lobe and spreading into the temporal and occipital lobes, AF is a fiber tract that stems from the caudal part of the superior temporal gyrus and extends to the lateral prefrontal cortex, the superior and the middle frontal regions. Limbic system fibers are the cyngulum fibers that project both posteriorly from the cingulate gyrus to the entorhinal cortex, temporal lobe, and anteriorly to the premotor, prefrontal regions and striatum. The fornix connects the hippocampus to the mamillary bodies, nucleus accumbens, medial prefrontal cortex, and septal regions, thus this fiber serves as the main output and input pathway for hippocampus. Thalamic radiations are projection fibers that provides a functional loop between the cerebral cortex and the thalamus; they converged into the internal capsule, located between the putamen and the thalamus-caudate nucleus regions 5.
Changes in WM integrity were found in chronic psychosis, first-episode psychosis and patients at ultra-high risk for psychosis, they may play a role in the primary pathophysiology, as opposed to being a result of secondary disease processes. These changes have been correlated with specific cognitive deficits as well as clinical symptoms, suggesting that biological changes may underlie these clinical factors in patients.
Previous DTI studies assessing the impact of WM disruptions on the disease process have had mixed results. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in psychosis patients.
The main findings in patients at ultra-high risk for psychosis were a decreased FA in inferior FOF, temporal lobe WM, frontal lobe WM. They seem to have predictive value of onset of psychosis in high-risk individuals. Other studies in ultra-high risk patients showed lower FA in anterior CR, corticospinal tracts, SLF, ILF, UF, CC and C. In addition, increase of FA values was seen in anterior C, left UF, AF, frontal lobe WM, right fornix and brain stem. The prediction of psychosis is a major topic in research and olds the hope for early intervention and prevention of full development of the illness, improving outcome and preserving WM integrity.
Decreases of FA in different tracts in patients at first-episode psychosis support notion of early disconnectivity between brain regions: the most burned were CC, UF, ILF, SLF, inferior FOF, temporal lobe WM, parietal lobe WM and left frontal lobe WM. White matter abnormalities were also observed in C, occipital lobe, CI, corticospinal tracts, cerebral peduncles and fornix. None of the studies included showed increased FA in patients with first-episode psychosis.
DTI abnormalities in first-episode patients are less robust than in chronic patients, suggesting that progression to more extensive abnormalities occurs after illness onset; there are also indications for accelerated aging effects in psychosis.
FA reductions were found in patients with chronic psychosis in CC, C, UF, left ILF, inferior FOF, SLF, FMN, FMJ, CR, corticospinal tracts, anterior CI, TR, temporal lobe WM, occipital lobe WM and frontal lobe WM. Changes in WM integrity have been reported also in left AF, superior FOF, fornix and hippocampus.
White matter tracts that were reported to have increased FA in almost one study include brain stem, right frontal lobe WM, left occipital lobe WM, insula, CI, cerebellum, inter-hemispheric and cortico-cortical tracts.
Of the included studies, 13 did not report group differences in anisotropy measures between patients and controls (3 in ultra-high risk patients, 8 in first-episode psychosis, 2 in chronic psychosis).
38 of the included studies (7 in UHR, 12 in FEP, 19 in SZ) found significant correlations between clinical or cognitive variables and FA values in some WM tracts. 3 studies showed a negative correlation between the severity of positive symptoms and FA values in some WM tracts like temporal lobe WM, right anterior C, right frontal lobe WM, cingulated gyrus WM, left fornix, right anterior and posterior limb of CI, left UF, left SLF, fibers connecting the rostral with the caudal anterior CG, bilateral inter-hemispheric and cortico-cortical connections, cerebellum and brain stem. Regarding to hallucinatory experience a positive correlation was found with FA values in right AF, while severity of delusions was associated with FA values in right ILF.
In 3 studies negative symptoms were correlated negatively with FA values in some WM tracts including C, bilateral UF, CC, TL, OL, PL, FL and fibers connecting C with parahippocampal cortex; in one paper a positive correlation was found between negative symptoms and WM integrity in right I.
FA values showed a relation with clinical symptoms in right UF, CC, left ILF, left anterior limb of CI, FMJ, right AC, frontal connectivity and bilateral AF.
Cognitive function was found to be related with WM deficits in left and right UF, right CE, SLF, right AC, frontal connectivity, right anterior limb of CI (this one was found to be proportional to performance on measures of spatial and verbal declarative/episodic memory). Left thalamic FA values correlated with spatial working memory deficits. Fractional anisotropy in right rostral middle GF-striatum tract correlated positively with the number of WCST categories completed; FA reduction in LG predicted impaired processing speed while FA in left C correlated with orienting of attention. According to Marenco et al. 82 the total thalamo-cortical connectivity to PFR predicted working memory task performance.
On the contrary, according to Lee et al.65 FA in right inferior FOF had a positive relation with negative, positive symptoms and all the items of WCST; similarly, according to Choi et al.88 anterior commissure integrity correlated negatively with decision making and positively with total positive symptoms score. In UHR patients increase in FA in CC was found to be correlated with improvement in subthreshold positive symptoms while, in other samples, patients later developing psychosis had lower FA values in several tracts. In less numerous papers FA values did not differ between UHR patients that developed or not a psychotic disorder.
Functional deterioration in UHR was predicted by lower FA values in H and ILF, Goghari et al.32 didn’t find significant relationship between FA and global functioning.
On the other side, no correlation with clinical/cognitive measures were found in 8 of the studies included (2 in UHR, 3 in FEP, 3 in SZ).
Antonius et al.89 studied the relation between symptoms unawareness and WM abnormalities, suggesting that misattribution of symptoms may be implied by loss of WM integrity in right LG, TL and right precuneus.
The impact of medications on WM integrity is far from well understood. The vast majority of patients participating in DTI studies to date have been on antipsychotic medication treatment. Although medication dose or cumulative exposure do not correlate with FA in most studies; some studies reported positive findings: according to Marques et al.72 patients non-responders to treatment at baseline showed lower FA in UF, C, CC; additionally, in the same sample after 12 weeks increase in FA positively correlated to antipsychotic exposure.
Interestingly, in 2 studies FA values have been associated with metabolic measures like greater levels of LDL or polyunsaturated fatty acid concentration.
Several studies have shown age-related reduction in FA in schizophrenia, whereas other studies did not replicate this relationship. While some studies that examined correlations with age failed to identify a significant effect, 5 of the included papers showed significant negative correlation between FA and age. Additionally, SZ adults showed most FA reduction in SNC posterior region, while SZ adolescents had most FA reduction in SNC anterior region. Karlsgodt et al.14 found the absence of age-associated increase in FA in H and ILF in UHR patients.
Some studies pointed out the effect of some socio-demographic variables like gender, duration of untreated psychosis, duration of illness and age of onset on WM changes. Older age of onset tended to be associated with higher FA in ventral CI and ventral temporo-occipital WM, while adolescent-onset psychosis subjects showed WM anomalies in short association fibers connecting superior temporal gyrus and Heschl’s gyrus; suggesting that symptoms associated with TL WM anomalies including auditory hallucinations would present before FL WM symptoms including problem in executive functioning. Later age of onset was found in SZ born in winter months, SZ born in summed had lower FA in CC, bilateral inferior FOF, bilateral UF, right anterior and bilateral posterior CR, left posterior C, left posterior TR, bilateral SLF, bilateral CST and FMJ. Filippi et al. 90 found abnormalities in right anterior and posterior limb of CI, bilateral inter-hemispheric and cortico-cortical connections, cerebellum and brain stem to be related with a longer duration of untreated psychosis. Cui et al.100 showed no correlation of WM anomalies with duration of illness. No significant associations were found between FA and QI in 2 papers, but in another one SZ patients had FA values proportional to QI and differences between smoking and non-smoking SZ were no longer significant after QI correction.
Focusing particularly on patients outcome, increase in FA values in affected tracts was predictive of improvement in symptoms and good outcome, while greater WM changes in some of these tracts, like bilateral UF and bilateral SLF, were associated with poor outcome.
There is a need to better understand the relationship between neural changes with clinical manifestations, cognitive and social functioning and outcome. Understanding the progression of these changes over the span of the illness is important whilst taking into account the possible confounding effects of age, age of onset, duration of illness, sex, and treatment. This will potentially allow better staging of illness, identification of biomarkers for monitoring course of the illness as well as response to treatment.
In conclusion, despite heterogeneity of DTI findings in psychosis, there is mounting evidence of disruptions of white matter integrity in cortical-subcortical brain regions, as well as associative and commissural tracts, highlighting neural changes in patients affected by or at high-risk for psychosis.
Future studies need to validate these findings in larger samples of subjects and in different populations as well as chart the progress of these cerebral WM changes over time so as to better appreciate the trajectory with illness course, treatment and chronicity.
Particularly, it can be useful combining DTI studies to functional RMN methods in order to investigate mediating factors that will enhance our knowledge about pathophysiology of psychosis.
  1. Picchioni M, Murray RM. Schizophrenia. BMJ 2007; 335: 91-5.
  2. Miguel-Hidalgo JJ. Brain structural and functional changes in adolescents with psychiatric disorders. Int J Adolesc Med Health 2013; 25: 245-56.
  3. Benes F, Turtle M, Khan Y, Farol P. Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence and adulthood. Arch Gen Psichiatry 1994; 51: 477-84.
  4. Lenroot RK, Giedd JN. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 2006; 30: 718-29.
  5. Kuswanto CN, Teh I, Lee TS, Sim K. Diffusion tensor imaging findings of white matter changes in first episode schizophrenia: a systematic review. Clin Psychopharmacol Neurosci 2012; 10: 13-24.
  6. Peters BD, Blaas J, de Haan L. Diffusion tensor imaging in the early phase of schizophrenia: what have we learned? J Psychiatr Res 2010; 44: 993-1004.
  7. Pierpaoli C, Jezzard P, Basser PJ, Barnett A, Di Chiro G. Diffusion tensor MR imaging of the human brain. Radiology 1996; 201: 637-48.
  8. Kyriakopoulos M, Bargiotas T, Barker GJ, Frangou S. Diffusion tensor imaging in schizophrenia. Eur Psychiatry 2008; 23: 255-73.
  9. Katagiri N, Pantelis C, Nemoto T, et al. A longitudinal study investigating sub-threshold symptoms and white matter changes in individuals with an ‘at risk mental state’ (ARMS). Schizophr Res 2015; 162: 7-13.
 10. Bloemen O, de Koning MB, Schmitz N, et al. White-matter markers for psychosis in a prospective ultra-high-risk cohort. Psychol Med 2010; 40: 1297-304.
 11. Muñoz Maniega S, Lymer GK, Bastin ME, et al. A diffusion tensor MRI study of white matter integrity in subjects at high genetic risk of schizophrenia. Schizophr Res 2008; 106: 132-9.
 12. Camchong J, Lim KO, Sponheim SR, Macdonald AW. Frontal white matter integrity as an endophenotype for schizophrenia: diffusion tensor imaging in monozygotic twins and patients’ nonpsychotic relatives. Front Hum Neurosci 2009; 3: 35.
 13. Nakamura M, McCarley RW, Kubicki M, et al. Fronto-temporal disconnectivity in schizotypal personality disorder: a diffusion tensor imaging study. Biol Psychiatry 2005; 58: 468-78.
 14. Karlsgodt KH, Niendam TA, Bearden CE, Cannon TD. White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis. Biol Psychiatry 2009; 66: 562-9.
 15. Peters BD, Dingemans PM, Dekker N, et al. White matter connectivity and psychosis in ultra-high-risk subjects: a diffusion tensor fiber tracking study. Psychiatry Res 2010; 181: 44-50.
 16. Peters BD, de Haan L, Dekker N, et al. White matter fibertracking in first-episode schizophrenia, schizoaffective patients and subjects at ultra-high risk of psychosis. Neuropsychobiology 2008; 58: 19-28.
 17. Peters BD, Schmitz N, Dingemans PM, et al. Preliminary evidence for reduced frontal white matter integrity in subjects at ultra-high-risk for psychosis. Schizophr Res 2009; 111: 192-3.
 18. Bertisch H, Li D, Hoptman MJ, Delisi LE. Heritability estimates for cognitive factors and brain white matter integrity as markers of schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 885-94.
 19. Hazlett EA, Goldstein KE, Tajima-Pozo K, et al. Cingulate and temporal lobe fractional anisotropy in schizotypal personality disorder. Neuroimage 2011; 55: 900-8.
 20. Kyriakopoulos M, Perez-Iglesias R, Woolley JB, et al. Effect of age at onset of schizophrenia on white matter abnormalities. Br J Psychiatry 2009; 195: 346-53.
 21. Carletti F, Woolley JB, Bhattacharyya S, et al. Alterations in white matter evident before the onset of psychosis. Schizophr Bull 2012; 38: 1170-9.
 22. Benetti S, Pettersson-Yeo W, Allen P, et al. Auditory verbalm hallucinations and brain dysconnectivity in the perisylvian language network: a multimodal investigation. Schizophr Bull 2015; 41: 192-200.
 23. Hoptman JM, Nierenberg J, Bertisch HC, et al. A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia. Schizophr Res 2008; 106: 115-24.
 24. Smallman RP, Barkus E, Azadbakht H, et al. MRI diffusion tractography study in individuals with schizotypal features: a pilot study. Psychiatry Res 2014; 221: 49-57.
 25. Domen PA, Michielse S, Gronenschild E, et al. Microstructural white matter alterations in psychotic disorder: a family-based diffusion tensor imaging study. Schizophr Res 2013; 146: 291-300.
 26. Boos HB, Mandl RC, van Haren NE, et al. Tract-based diffusion tensor imaging in patients with schizophrenia and their non-psychotic siblings. Eur Neuropsychopharmacol 2013; 23: 295-304.
 27. Epstein KA, Cullen KR, Mueller BA, Robinson P, Lee S, Kumra S. White matter abnormalities and cognitive impairment in early-onset schizophrenia-spectrum disorders. J Am Acad Child Adolesc Psychiatry 2014; 53: 362-72. e1-2.
 28. DeRosse P, Nitzburg GC, Ikuta T, Peters BD, Malhotra AK, Szeszko PR. Evidence from structural and diffusion tensor imaging for frontotemporal deficits in psychometric schizotypy. Schizophr Bull 2015; 41: 104-14.
 29. Lener MS, Wong E, Tang CY, et al. White matter abnormalities in schizophrenia and schizotypal personality disorder. Schizophr Bull 2015; 41: 300-10.
 30. Lagopoulos J, Hermens DF, Hatton SN, et al. Microstructural white matter changes are correlated with the stage of psychiatric illness. Transl Psychiatry 2013; 3: e248.
 31. Jacobson S, Kelleher I, Harley M, et al. Structural and functional brain correlates of subclinical psychotic symptoms in 11-13 year old schoolchildren. Neuroimage 2010; 49: 1875-85.
 32. Goghari VM, Billiet T, Sunaert S, Emsell L. A diffusion tensor imaging family study of the fornix in schizophrenia. Schizophr Res 2014; 159: 435-40.
 33. von Hohenberg CC, Pasternak O, Kubicki M, et al. White matter microstructure in individuals at clinical high risk of psychosis: a whole-brain diffusion tensor imaging study. Schizophr Bull 2014; 40: 895-903.
 34. Pettersson-Yeo W, Benetti S, Marquand AF, et al. Using genetic, cognitive and multimodal neuroimaging data to identify ultra-high risk and first-episode psychosis at the individual level. Psychol Med 2013; 43: 2547-62.
 35. Epstein KA, Kumra S. White matter fractional anisotropy over two time points in early onset schizophrenia and adolescent cannabis use disorder: a naturalistic diffusion tensor imaging study. Psychiatry Res 2015; 232: 34-41.
 36. Mittal VA, Dean DJ, Bernard JA, et al. Neurological soft signs predict abnormal cerebellar-thalamic tract development and negative symptoms in adolescents at high-risk for psychosis: a longitudinal perspective. Schizophr Bull 2014; 40: 1204-15.
 37. DeRosse P, Ikuta T, Peters BD, Karlsgodt KH, Szeszko PR, Malhotra AK. Adding insult to injury: childhood and adolescent risk factors for psychosis predict lower fractional anisotropy in the superior longitudinal fasciculus in healthy adults. Psychiatry Res 2014; 224: 296-302.
 38. Skranes J, Vangberg TR, Kulseng S, et al. Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight. Brain 2007; 130 (Pt 3): 654-66.
 39. Gilmore J, Kang C, Evans DD, et al. Prenatal and neonatal brain structure and white matter maturation in children at high risk for schizophrenia. Am J Psychiatry 2010; 167: 1083-91.
 40. Alvarado-Alanis P, León-Ortiz P, Reyes-Madrigal F, et al. Abnormal white matter integrity in antipsychotic-naive first-episode psychosis patients assessed by a DTI principal component analysis. Schizophr Res 2015; 162: 14-21.
 41. Chan WY, Yang GL, Chia MY, et al. White matter abnormalities in first-episode schizophrenia: a combined structural MRI and DTI study. Schizophr Res 2010; 119: 52-60.
 42. Karlsgodt KH, van Erp TG, Poldrack RA, Bearden CE, Nuechterlein KH, Cannon TD. Diffusion tensor imaging of the superior longitudinal fasciculus and working memory in recent-onset schizophrenia. Biol Psychiatry 2008; 63: 512-8.
 43. Mendelsohn A, Strous RD, Bleich M, Assaf Y, Hendler T. Regional axonal abnormalities in first episode schizophrenia: preliminary evidence based on high b-value diffusion-weighted imaging. Psychiatry Res 2006; 146: 223-9.
 44. Gasparotti R, Valsecchi P, Carletti F, et al. Reduced fractional anisotropy of corpus callosum in first-contact, antipsychotic drug-naive patients with schizophrenia. Schizophr Res 2009; 108: 41-8.
 45. Melicher T, Horacek J, Hlinka J, et al. White matter changes in first episode psychosis and their relation to the size of sample studied: a DTI study. Schizophr Res 2015; 162: 22-8.
 46. White T, Magnotta VA, Bockholt HJ, et al. Global white matter abnormalities in schizophrenia: a multisite diffusion tensor imaging study. Schizophr Bull 2011; 37: 222-32.
 47. Wang Q, Deng W, Huang C, et al. Abnormalities in connectivity of white matter tracts in patients with familial and non-familial schizophrenia. Psychol Med 2011; 41: 1691-700.
 48. Tang J, Liao Y, Zhou B, et al. Abnormal anterior cingulum integrity in first episode, early-onset schizophrenia: a diffusion tensor imaging study. Brain Res 2010; 1343: 199-205.
 49. Begré S, Federspiel A, Kiefer C, Schroth G, Dierks T, Strik WK. Reduced hippocampal anisotropy related to anteriorization oh alpha EEG in schizophrenia. Neuroreport 2003; 14: 739-42.
 50. Cheung V, Chiu CP, Law CW, et al. Positive symptoms and white matter microstructure in never-medicated first episode schizophrenia. Psychol Med 2011; 41: 1709-19.
 51. Moriya J, Kakeda S, Abe O, et al. Gray and white matter volumetric and diffusion tensor imaging (DTI) analyses in the early stage of first-episode schizophrenia. Schizophr Res 2010; 116: 196-203.
 52. Price G, Cercignani M, Parker GJ, et al. White matter tracts in first-episode psychosis: a DTI tractography study of the uncinate fasciculus. Neuroimage 2008; 39: 949-55.
 53. Szeszko PR, Robinson DG, Ashtari M, et al. Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia. Neuropsychopharmacology 2008; 33: 976-84.
 54. Pérez-Iglesias R, Tordesillas-Gutiérrez D, Barker GJ, et al. White matter defects in first episode psychosis patients: a vowelwise analysis of diffusion tensor imaging. Neuroimage 2010; 49: 199-204.
 55. Bijanki KR, Hodis B, Magnotta VA, Zeien E, Andreasen NC. Effects of age on white matter integrity and negative symptoms in schizophrenia. Schizophr Res 2015; 161: 29-35.
 56. Luck D, Malla AK, Joober R, Lepage M Disrupted integrity of the fornix in first-episode schizophrenia. Schizophr Res 2010; 119: 61-4.
 57. Kong X, Ouyang X, Tao H, et al. Complementary diffusion tensor imaging study of the corpus callosum in patients with first-episode and chronic schizophrenia. J Psychiatry Neurosci 2011; 36: 120-5.
 58. Schneiderman JS, Buchsbaum MS, Haznedar MM, et al. Age and diffusion tensor anisotropy in adolescent and adult patients with schizophrenia. Neuroimage 2009; 45: 662-71.
 59. Chen L, Chen X, Liu W, et al. White matter microstructural abnormalities in patients with late-onset schizophrenia identified by a voxel-based diffusion tensor imaging. Psychiatry Res 2013; 212: 201-7.
 60. Friedman J, Tang C, Carpenter D, et al. Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients. Am J Psychiatry 2008; 165: 1024-32.
 61. Peters BD, Machielsen MW, Hoen WP, et al. Polyunsaturated fatty acid concentration predicts myelin integrity in early-phase psychosis. Schizophr Bull 2013; 39: 830-8.
 62. Hao Y, Liu Z, Jiang T, et al. White matter integrity of the whole brain is disrupted in first-episode schizophrenia. Neuroreport 2006; 17: 23-6.
 63. Cheung C, Cheung C, McAlonan GM, et al. A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia. Psychol Med 2008; 38: 877-85.
 64. Szeszko PR, Robinson DG, Ikuta T, et al. White matter changes associated with antipsychotic treatment in first-episod psychosis. Neuropsychopharmacology 2014; 39: 1324-31.
 65. Lee SH, Kubicki M, Asami T, et al. Extensive white matter abnormalities in patients with first-episode schizophrenia: a Diffusion Tensor Iimaging (DTI) study. Schizophr Res 2013; 143: 231-8.
 66. Price G, Cercignani M, Parker GJ, et al. Abnormal brain connectivity in first-episode psychosis: a diffusion MRI tractography study of the corpus callosum. Neuroimage 2007; 35: 458-66.
 67. Qiu A, Zhong J, Graham S, Chia MY, Sim K. Combined analyses of thalamic volume, shape and white matter integrity in first-episode schizophrenia. Neuroimage 2009; 47: 1163-71.
 68. Dekker N, Schmitz N, Peters BD, van Amelsvoort TA, Linszen DH, de Haan L. Cannabis use and callosal white matter structure and integrity in recent-onset schizophrenia. Psychiatry Res 2010; 181: 51-6.
 69. Quan M, Lee SH, Kubicki M, et al. White matter tract abnormalities between rostral middle frontal gyrus, inferior frontal gyrus and striatum in first-episode schizophrenia. Schizophr Res 2013; 145: 1-10.
 70. Szeszko P, Ardekani BA, Ashtari M, et al. White matter abnormalities in first-episode schizophreniaor schizoaffective disorder: a diffusion tensor imaging study. Am J Psychiatry 2005; 162: 602-5.
 71. Kyriakopoulos M, Vyas NS, Barker GJ, Chitnis XA, Frangou S. A diffusion tensor imaging study of white matter in early-onset schizophrenia. Biol Psychiatry 2008; 63: 519-23.
 72. Reis Marques T, Taylor H, Chaddock C, et al. White matter integrity as a predictor of response to treatment in first episode psychosis. Brain 2014; 137: 172-82.
 73. Lu HL, Zhou XJ, Keedy SK, Reilly JL, Sweeney JA. White matter microstructure in untreated first episode bipolar disorder with psychosis: comparison with schizophrenia. Bipolar Disord 2011; 13: 604-13.
 74. Luck D, Buchy L, Czechowska Y, et al. Fronto-temporal disconnectivity and clinical short-term outcome in first episode psychosis: a DTI-tractography study. J Psychiatr Res 2011; 45: 369-77.
 75. Peters BD, de Haan L, Vlieger EJ, Majoie CB, den Heeten GJ, Linszen DH. Recent-onset schizophrenia and adolescent cannabis use: MRI evidence for structural hyperconnectivity? Psychopharmacol Bull 2009; 42: 75-88.
 76. Palaniyappan L, Al-Radaideh A, Mougin O, Gowland P, Liddle PF. Combined white matter imaging suggests myelination defects in visual processing regions in schizophrenia. Neuropsychopharmacology 2013; 38: 1808-15.
 77. Nazeri A, Chakravarty MM, Felsky D, et al. Alterations of superficial white matter in schizophrenia and relationship to cognitive performance. Neuropsychopharmacology 2013; 38: 1954-62.
 78. Orfei MD, Piras F, Macci E, Caltagirone C, Spalletta G. The neuroanatomical correlates of cognitive insight in schizophrenia. Soc Cogn Affect Neurosci 2013; 8: 418-23.
 79. Roalf DR, Ruparel K, Verma R, Elliott MA, Gur RE, Gur RC. White matter organization and neurocognitive performance variability in schizophrenia. Schizophr Res 2013; 143: 172-8.
 80. Hatton SN, Lagopoulos J, Hermens DF, Hickie IB, Scott E, Bennett MR. White matter tractography in early psychosis: clinical and neurocognitive associations. J Psychiatry Neurosci 2014; 39: 417-27.
 81. Cullen KR, Wallace S, Magnotta VA, et al. Cigarette smoking and white matter microstructure in schizophrenia. Psychiatry Res 2012; 201: 152-8.
 82. Marenco S, Stein JL, Savostyanova AA, et al. Investigation of anatomical thalamo-cortical connectivity and FMRI activation in schizophrenia. Neuropsychopharmacology 2012; 37: 499-507.
 83. Yan H, Tian L, Yan J, et al. Functional and anatomical connectivity abnormalities in cognitive division of anterior cingulate cortex in schizophrenia. PLoS One 2012; 7: e45659.
 84. Camchong J, MacDonald AW 3rd, Bell C, Mueller BA, Lim KO. Altered functional and anatomical connectivity in schizophrenia. Schizophr Bull 2011; 37: 640-50.
 85. de Weijer AD, Mandl RC, Diederen KM, et al. Microstructural aterations of the arcuate fasciculus in schizophrenia patients with frequent auditory verbal hallucinations. Schizophr Res 2011; 130: 68-77.
 86. Abdul-Rahman MF, Qiu A, Sim K. Regionally specific white matter disruptions of fornix and cingulum in schizophrenia. PLoS One 2011; 6: e18652.
 87. Ardekani BA, Tabesh A, Sevy S, Robinson DG, Bilder RM, Szeszko PR. Diffusion tensor imaging reliably differentiates patients with schizophrenia fron healthy volunteers. Hum Brain Mapp 2011; 32: 1-9.
 88. Choi H, Kubicki M, Whitford TJ, et al. Diffusion tensor imaging of anterior commissural fibers in patients with schizophrenia. Schizophr Res 2011; 130: 78-85.
 89. Antonius D, Prudent V, Rebani Y, et al. White matter integrity and lack of insight in schizophrenia and schizoaffective disorder. Schizophr Res 2011; 128: 76-82.
 90. Filippi M, Canu E, Gasparotti R, et al. Patterns of brain structural changes in first-contact, antipsychotic drug-naive patients with schizophrenia. AJNR Am J Neuroradiol 2014; 35: 30-7.
 91. Sugranyes G, Kyriakopoulos M, Dima D, et al. Multimodal analyses identify linked functional and white matter abnormalities within the working memory network in schizophrenia. Schizophr Res 2012; 138: 136-42.
 92. Wagner G, De la Cruz F, Schachtzabel C, et al. Structural and functional dysconnectivity of the fronto-thalamic system in schizophrenia: a DCM-DTI study. Cortex 2015; 66: 35-45.
 93. Balevich EC, Haznedar MM, Wang E, et al. Corpus callosum size and diffusion tensor anisotropy in adolescents and adults with schizophrenia. Psychiatry Res 2015; 231: 244-51.
 94. Garver DL, Holcomb JA, Christensen JD. Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia. Int J Neuropsychopharmacol 2008; 11: 49-61.
 95. Rosenberger G, Kubicki M, Nestor PG, et al. Age-related deficits in fronto-temporal connections in schizophrenia: a diffusion tensor imaging study. Schizophr Res 2008; 102: 181-8.
 96. Skelly LR, Calhoun V, Meda SA, Kim J, Mathalon DH, Pearlson GD. Diffusion tensor imaging in schizophrenia: relationship to symptoms. Schizophr Res 2008; 98: 157-62.
 97. Nestor PG, Kubicki M, Spencer KM, Niznikiewicz M, McCarley RW, Shenton ME. Attentional networks and cingulum bundle in chronic schizophrenia. Schizophr Res 2007; 90: 308-15.
 98. Liu H, Fan G, Xu K, Wang F. Changes in cerebellar functional connectivity and anatomical connectivity in schizophrenia: a combined resting-state functional MRI and diffusion tensor imaging study. J Magn Reson Imaging 2011; 34: 1430-8.
 99. Caprihan A, Abbott C, Yamamoto J, et al. Source-based morphometry analysis of group differences in fractional anisotropy in schizophrenia. Brain Connect 2011; 1: 133-45.
100. Cui L, Chen Z, Deng W, et al. Assessment of white matter abnormalities in paranoid schizophrenia and bipolar mania patients. Psychiatry Res 2011; 194: 347-53.
101. Levitt JJ, Kubicki M, Nestor PG, et al. A diffusion tensor imaging study of the anterior limb of the internal capsule in schizophrenia. Psychiatry Res 2010; 184: 143-50.
102. Knöchel C, Stäblein M, Storchak H, et al. Multimodal assessments of the hippocampal formation in schizophrenia and bipolar disorder: evidences from neurobehavioral measures and functional and structural MRI. Neuroimage Clin 2014; 6: 134-44.
103. Whitford TJ, Lee SW, Oh JS, et al. Localized abnormalities in the cingulum bundle in patients with schizophrenia: a Diffusion Tensor tractography study. Neuroimage Clin 2014; 5: 93-9.
104. Mc-Carthy Jones S, Oestreich LK, Australian Schizophrenia Research Bank, Whitford TJ. Reduced integrity of the left arcuate fasciculus is specially associated with auditory verbal hallucinations in schizophrenia. Schizophr Res 2015; 162: 1-6.
105. Sasamoto A, Miyata J, Kubota M, et al. Global association between cortical thinning and white matter integrity reduction in schizophrenia. Schizophr Bull 2014; 40: 420-7.
106. Kawashima T, Nakamura M, Bouix S, et al. Uncinate fasciculus abnormalities in recent onset schizophrenia and affective psychosis: a diffusion tensor imaging study. Schizophr Res 2009; 110: 119-26.
107. Hatton SN, Lagopoulos J, Hermens DF, Hickie IB, Scott E, Bennett MR. Short association fibres of the insula-temporoparietal junction in early psychosis: a diffusion tensor imaging study. PLoS One 2014; 9: e112842.
108. Zou L, Xie JX, Yuan HS, Pei XL, Dong WT, Liu PC. Diffusion tensor imaging study of the anterior limb of internal capsules in neuroleptic-naive schizophrenia. Acad Radiol 2008; 15: 285-9.
109. Giezendanner S, Walther S, Razavi N, et al. Alterations of white matter integrity related to the season of birth in schizophrenia: a DTI study. PLoS One 2013; 8: e75508.
110. Tang CY, Friedman J, Shungu D, et al. Correlations between Diffusion Tensor Imaging (DTI) and agnetic Resonance Spectroscopy (1H MRS) in schizophrenic patients and normal controls. BMC Psychiatry 2007; 7: 25.
111. Flügel D, Cercignani M, Symms MR, et al. Diffusion tensor imaging findings and their correlation with neuropsycological deficits in patients with temporal lobe epilepsy and interictal psychosis. Epilepsia 2006; 47: 941-4.
112. Mao LY, Ding J, Peng WF, et al. Disease duration and arcuate fasciculus abnormalities correlate with psychoticism in patients with epilepsy. Seizure 2011; 20: 741-7.
113. Cocchi L, Harding IH, Lord A, Pantelis C, Yucel M, Zalesky A. Disruption of structure-function coupling in the schizophrenia connectome. Neuroimage Clin 2014; 4: 779-87.
114. Zhong J, Wu S, Zhao Y, et al. Why psychosis is frequently associated with Parkinson’s disease? Neural Regen Res 2013; 8: 2548-56.